Pancreatic ductal adenocarcinoma (PDAC) is one of the most prevalent neoplastic disorders with poor prognosis. The etiology of the disease is multifactorial: with environmental, pre existing medical, and hereditary factors all playing a role. The precursor lesions are pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and familial pancreatic cancer, among others. The incidence is 10–12 cases per 100,000, and it is the fourth leading cause of death from cancer in the US. It usually occurs between 60–80 years of age, with a slight male predominance – and is more commonly seen in Black populations in the US. Typical symptoms include painless jaundice and weight loss.
There is an increased importance of molecular diagnostics in every organ system, and the pancreas is not far behind. As we know, PDAC is a biologically aggressive malignancy with poor prognosis. The tumors can present clinically benign as back pain, jaundice, and weight loss. Even with advanced surgical and chemotherapeutic options, the survival rate is less than 10 percent. Typically, diagnosis is made on endoscopic ultrasound-guided fine needle aspiration. However, whole-genome sequencing has unfolded the genomic landscape of PDAC, allowing for a whole new approach to its diagnosis.
Pancreas: Adenocarcinoma vs. Normal Ductal Epithelium on FNA, Ed Uthman / Flickr.com / CC BY
The key driving mutations are KRAS, TP53, SMAD4, and CDKN2A. Other genes, including ARID1A, KDM6A, MLL3, TGFBR2, RBM10, and BCORL1, are found in less than 10 percent of tumors. Gene alterations associated with targeted therapy, such as ERBB2 amplification, BRAF gene fusions and mutations, and DNA damage repair genes mutations like BRCA1, BRCA2, or PALB2, are also found in a small percentage of PDAC patients. Advances in molecular pathology in PDAC help in the advent of targeted therapy, which is more effective.
Without doubt, KRAS is the major driving mutation and target for therapies. Thus, KRAS-related molecules and pathways are research hotspots. Many CAR-T targets have been identified, including MSLN, CEA, CD133, Tn/STn, B7-H3, KRAS G12D, PD-1 and HER2. Meanwhile, antibody drug conjugates and the bispecific T-cell engager platform are able to target PDAC cells with precision. Immune checkpoint blockades such as PDL1 also have a role that is related to the number of genetic mutations; namely, the lower the mutations the more it will be resistant to PDL1 inhibitors. All these targeted therapies would aid in providing diverse therapeutic options for pancreatic ductal adenocarcinoma and improve its poor prognosis.
With appropriate techniques and methodologies, molecular pathology can help realize personalized treatment options for PDAC – with the hope of increasing long term survival for patients who currently have a dismal prognosis.
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